Treatment of cancer is limited by affordability of patients in the many developing countries including India. Generic drug manufacturers have responded to this scenario by making drugs available at affordable costs, often at less than 10% the cost of the original brand. In our practice, it is found that there is a three-fold higher prescription of generic brands compared to innovator, accompanied by cost savings of up to 80% per prescription. Unfortunately, the regulatory environment prevailing in India is not geared to ensure satisfactory quality of generic products. The standards set by the regulatory agencies for establishing equivalence of generics vis-ΰ-vis the innovator product allow anticancer generics to enter markets without undergoing clinical evaluation. Many drug manufacturing units in India flout good manufacturing practice norms, which was evident during the center for drug evaluation and research classifications inspection in the year 2006. Inferior drugs have therefore, made their way into the Indian markets, compromising the quality of care. The system of drug manufacturing and marketing approval needs a major overhaul, including regular inspection of manufacturing facilities. Bioequivalence should be made mandatory for all oral formulations. Unless these measures are rigidly implemented, the benefits of generic substitution would be seriously undermined.

Optimal cancer therapy in India, like in other developing countries, is limited by affordability of patients. It is an out of pocket expenditure for many patients since more than 90% of Indians do not have health insurance. Generally, innovator cancer drugs are very highly priced, owing to the high-cost involved in the clinical development. Local pharmaceutical companies have responded by manufacturing affordable generics. A number of generic cancer drugs are marketed in India and used an interchangeably with the innovator. Generics would often cost significantly less than the original brand, sometimes providing up to 90% savings in the cost. [1],[2] This paper highlights the key issues related to approval of generic anticancer drugs in India and discusses how a slightly proactive regulations and surveillance could improve the overall quality of generic drugs available for use in cancer.

» Discussion

The process of regulatory approval for marketing cancer generics in India is not very robust. The Central Drugs Standard Control Organization (CDSCO) in its "Draft Guidelines for Bioavailability/Bioequivalence Studies on Conventional and Extended Release Dosage Forms" has categorically stated "in-vitro dissolution studies are required where bioequivalence is not applicable, e.g., anticancer drugs, drugs which are systemically not absorbed, etc ." [3] In contrast, the US Food and Drug Administration (FDA) has lay down clear guidelines for bioequivalence studies of anticancer drugs. The guidelines clarify that bioequivalence studies should be conducted in the cancer patients in a manner that it should not change patients' normal therapy that it should be flexible about the dose (but not dosage strength) used for each patient in the study, and steady-state studies should be considered, if necessary. [4] Although, companies that make high quality drugs are not an exception, the CDSCO guidelines allow unscrupulous manufacturers to bring sub-standard drugs into the market. Thus, standard of care may not be uniform when a generic is substituted for the original, which is further compounded several folds by the large number of generics available in the market. In the absence of clinical data demonstrating similarity of the generics to the innovator, oncologists often harbor doubts about the quality of generic products, which defeats the purpose of introducing generics in the market. Therefore, in spite of the cost savings associated with a generic substitution, most centers leave the choice to patients, who in turn select one brand over the other depending on affordability.

With an average per capita income of a little over $1000, India is dominated by middle income segment, typified by lack of penetration of health insurance. Generic substitution is one mechanism of curtailing prescription drug expenditures. Patients often value the cost savings from generic purchases more than any probable quality premiums offered by branded drugs. The safety and efficacy of treatment could be compromised in the bargain. For instance, a study comparing the pharmaceutical quality of 31 docetaxel generics versus Taxotere (Sanofi-Aventis, France) was published by a French group in the year 2008. [5] Ten of them were Indian brands, out of which only three brands contained average mass of docetaxel exceeding 90% of expected while nine brands had impurity levels greater than 3%. Thus, generic substitution may fail to sustain the dose density of treatment or expose patients to potentially harmful impurities.

Access to substandard products could be due to incomplete and inconsistent standards, ineffective controls or lack of enforcement. [6] The US FDA ensures continued implementation of good manufacturing practices (GMPs) by conducting surprise inspections of drug manufacturing plants. Unless such practices are rigidly followed, manufacturers of active pharmaceutical ingredients (APIs) and drug formulations may attempt to cut manufacturing cost by resorting to slapdash practices. In fact, this is evident from the center for drug evaluation and research classifications inspection of Indian drug manufacturing facilities during the fiscal year 2006 wherein several GMP deficiencies in production, quality, and laboratory control systems were observed and voluntary or official action was indicated in 60% and 6% cases respectively. Thus, a combination of lenient policies and lack of vigilance may lead to poor quality of generics entering the markets.

[Table 1] lists 15 commonly used drugs in the oncology comparing the cost of the innovators and generics for one cycle of treatment or 1 month's supply of standard dose. Savings from generic substitution range from 36.67% to 81.21%. The greatest saving is for the frequently used oncology drug, docetaxel. The cost of one cycle of docetaxel for a breast cancer patient amounts to Rs. 43,333 for Taxotere as against Rs. 8,138 for the lowest priced generic formulation available in our pharmacy. This is a very attractive proposition for patients with modest income and lack of insurance cover, and perhaps the only way to receive the "standard of care". An audit conducted in September 2009 to find out the prevalence of generic substitution for the 15 drugs listed in the table revealed interesting statistics. The proportion of generics prescriptions ranged from 0% to 100% (median = 64.28%; interquartile range (IQR) = 37.6-81.2). The prescription ratio for generic to original was of the order 3:1 [Table 2]. This data underscores the fact that (1) generic substitution results in substantial cost saving and (2) generic substitution are highly prevalent in oncology practice. Although, the prevalence of generic substitution observed in our hospital in a given month may not be representative of the national scenario, it is reasonable to assume that the error would probably be on the side of underestimation, because, generics are likely to be prescribed more in smaller towns, and cities with a lower per capita income. Unfortunately, the credibility of most of these generics is not proven beyond doubt and clinical pharmacokinetic data for oral formulations is lacking.

Generally, anticancer drugs have a narrow therapeutic index. Generic manufacturers should provide data on pharmaceutical equivalence i.e., same molar concentration of the API vis-ΰ-vis the originator for drugs that are administered parenterally as a solution. For drugs administered orally, bioequivalence studies are necessary to prove that the rate and extent of absorption of a drug from the generic formulation is comparable to the originator. [7] The bioequivalence limits recommended by the most regulatory agencies is between 80% and 125% of the area under the concentration-time curve of the reference formulation. Many regulatory agencies including the European Medicinal Agency recommend a stricter acceptance interval (90-111%) for drugs with a narrow therapeutic index including, anticancer drugs. [8] It is time, the Indian Regulatory Agency, the Drugs Controller General of India, took cognizance of this fact and formulated rigorous guidelines for the approval of oncology generics in the country.

» Conclusion

Bioequivalence studies should be made mandatory before marketing approval could be granted for orally administered anticancer drugs. In addition, periodic and surprise inspections of the API and formulation units should be conducted to ensure unremitting supply of high quality drugs, long after bioequivalence is established. This will instill greater confidence in the generic formulations of antineoplastics among the end users.

» Acknowledgment

We are thankful to the pharmacy staff at Tata Memorial Hospital for their kind help during the audit.

Singal GL, Nanda A, Kotwani A. A comparative evaluation of price and quality of some branded versus branded-generic medicines of the same manufacturer in India. Indian J Pharmacol 2011;43:131-6. [PUBMED]